Chromatin-mediated anticipatory control of type I interferon production in plasmacytoid dendritic cells

  • Immunity. 2026 Feb 10;59(2):270-287.e11. doi: 10.1016/j.immuni.2025.12.005.
Nicholas M Adams  1 ,  Aleksandra Galitsyna  2 ,  Ioanna Tiniakou  1 ,  Eduardo Esteva  3 ,  Ai C Ra  4 ,  Simon Ullrich  5 ,  Stephen T Yeung  6 ,  Yanjun Tan  1 ,  Joseph N Pucella  1 ,  Igor Dolgalev  7 ,  David E Levy  1 ,  Kamal M Khanna  8 ,  Irina Solovei  5 ,  Leonid A Mirny  9 ,  Boris Reizis  10
Affiliations
  • 1. Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 2. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 3. Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 4. Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 5. Biozentrum, Ludwig Maximilians University Munich, 82152, Planegg-Martinsried, Germany.
  • 6. Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 7. Cellular Analytics Laboratory, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 8. Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
  • 9. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
  • 10. Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA. Electronic address: [email protected].
PMID: 41672043 DOI: 10.1016/j.immuni.2025.12.005
Abstract

Type I interferons (IFN-I), including IFN-β and multiple IFN-α subtypes, are key Antiviral proteins encoded within a single large locus. Here, we studied how the chromatin organization of this locus controls cell-type-specific IFN-I responses. The professional IFN-I-producing plasmacytoid dendritic cells (pDCs) simultaneously induced nearly all IFN-I subtypes across the locus. During pDC differentiation, the IFN-I locus translocated into the active intranuclear chromosomal compartment. It also underwent cohesin-dependent reorganization of its three-dimensional chromatin structure; accordingly, IFN-I production by pDCs was cohesin dependent. The promoters of most IFN-I genes harbored open chromatin peaks specifically in pDCs. The preemptive intranuclear translocation and promoter opening of IFN-I genes in pDCs were mediated by the pDC-enriched transcription factor interferon regulatory factor (IRF)8. Several IRF8- and/or cohesin-binding regulatory regions within the IFN-I locus facilitated IFN-I gene induction in pDCs, as confirmed by single-cell multiome analysis. Thus, the unique IFN-I-producing capacity of pDCs is facilitated by anticipatory chromatin organization imparted by IRF8 and cohesin.

Keywords
IRF8; chromatin; cohesin; plasmacytoid dendritic cells; type I interferon.
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